What if people could stay healthier, stronger, and mentally sharper as they grow older—not by treating diseases one by one but by slowing a biological process that drives aging itself? A new University of Rochester –led research effort will test whether a drug originally developed to treat HIV can quiet a chronic immune response triggered by the body’s own DNA, to help preserve overall health and function later in life.
The project is supported by a contract of up to approximately $22 million over five years from the Advanced Research Projects Agency for Health (ARPA-H), a federal agency created to support high-impact biomedical projects that could lead to transformative advances in health. Its highly competitive awards are designed to accelerate bold ideas that, if successful, could reshape how medicine approaches major health challenges. The URochester team is one of several selected by the agency’s PROactive Solutions for Prolonging Resilience (PROSPR) program.
The URochester effort is led by Vera Gorbunova , the Doris Johns Cherry Professor in the Department of Biology and currently co-director of the Rochester Aging Research (RoAR) Center and the Upstate NY Comparative Biology of Aging Nathan Shock Center , and brings together URochester researchers Andrei Seluanov from the River Campus, Kathi Heffner from the School of Nursing and co-director of the University’s Resilience Research Center , and Annette Medina-Walpole from the Medical Center , along with collaborators from Brown University, University of Connecticut, The University of Texas Medical Branch, University of Texas Health Houston, University of Nebraska, and Transposon Therapeutics.
“Aging underlies many chronic diseases, but it’s rarely targeted directly,” Gorbunova says. “This project builds on the University of Rochester’s long-standing leadership in aging research and gives us a unique opportunity to partner with other leading institutions to address one of the root causes of age-related decline.”
While scientists know that aging underlies many chronic diseases, the mechanisms driving this decline are poorly understood. One of the drivers may be hidden in our DNA: as people grow older, their cells can begin to mistake parts of their own genetic material for viral threats, triggering chronic inflammation that contributes to physical and cognitive decline.
The project—one of the first and most comprehensive efforts to test an intervention aimed directly at the biological mechanisms of aging—will test whether this internal “false alarm” can be safely reduced, helping older adults stay healthier for longer.
“The work being led by Professor Gorbunova is an excellent example of the ways in which large-scale public and private partnerships can address some of the most pressing challenges of human health and well-being,” says University President Sarah Mangelsdorf. “We’re grateful to Congress and our delegation, in particular, for their continued support of ARPA-H and the high-impact, transformative research it funds. We deeply appreciate ARPA-H and its recognition of Professor Gorbunova’s research and of the University of Rochester’s leadership in biomedical science and its application to human health.”
A hidden driver of aging
The research focuses on retrotransposons, virus-like sequences called selfish genetic elements that make up a large portion of the human genome. Unlike actual viruses, transposons cannot exit the cell and infect other cells, but they seek to propagate themselves within the host DNA. Transposons are normally kept dormant, but research over the past decade by Gorbunova and her colleagues has shown that retrotransposons become increasingly active with age, leading to inflammation that contributes to tissue decline.
“When we are young, our cells are good at keeping retrotransposons suppressed,” Gorbunova says. “As we age, that control weakens, and the immune system begins to respond as if the body is under viral attack.”
This kind of persistent, age-related immune response has been linked to a wide range of age-related diseases, such as neurodegeneration, cancer, diabetes, and autoimmune diseases. Gorbunova’s lab was among the first to show that LINE-1 retrotransposons can directly activate interferon signaling —the same antiviral defense system cells use to detect viral infections—creating a “false alarm” in the form of age-related inflammation.
“We have known for years that non-infection related inflammation increases with age and is linked to poor aging outcomes,” says Andrew Brack, ARPA-H program manager and creator of the PROSPR program. “Because LINE-1 retrotransposons have recently been reported to increase inflammation as we age, we are excited about the possibility that anti-retroviral therapies, which have the added benefit of a long history of safety in non-diseased populations, will extend healthspan.”
From discovery to intervention
Building on those discoveries, the ARPA-H–funded project will test whether a drug originally developed to treat HIV can suppress retrotransposon activity and reduce biological aging. The drug, TPN-101 (also known as Censavudine), inhibits reverse transcriptase—an enzyme that retrotransposons rely on to replicate.
In earlier preclinical studies, similar drugs reduced interferon signaling and chronic inflammation associated with aging. The new project will extend that work by testing long-term treatment in animal models, followed by a randomized clinical trial in humans. Heffner will lead the clinical trial.
“Translating the Gorbunova lab's pioneering discoveries into human clinical trials is an extraordinary opportunity to turn fundamental aging science into therapies that could meaningfully improve health in later life,” says Heffner, who collaborates with Gorbunova and Seluanov on the executive committee of the University’s Aging Institute, led by Medina-Walpole.
The clinical phase of the study will enroll 200 healthy adults ages 60 to 65, who will receive either Censavudine or a placebo for 48 weeks. The researchers will assess changes in intrinsic capacity, a World Health Organization framework that includes mobility, cognition, vitality, sensory function, and psychological health, along with molecular markers of biological aging, physical performance, and overall health.
The study could help pave the way for therapies designed to preserve overall health and function as people grow older.
“Our hope is that by dialing down retrotransposons, we can help people remain healthier, stronger, and mentally sharper as they age,” Gorbunova said. “That would be a profound shift in how we think about aging and intervention.”